Dataset Information

Splice variants of lysosome?associated membrane proteins 2A and 2B are involved in sunitinib resistance in human renal cell carcinoma cells.

ABSTRACT: Sunitinib, a tyrosine kinase inhibitor, is among the first?line treatments for metastatic or advanced stage renal cell carcinoma (RCC). However, patients with RCC develop resistance to sunitinib. We have previously demonstrated that lysosome?associated membrane protein 2 (LAMP?2), which has three splice variants with different functions (LAMP?2A, LAMP?2B, and LAMP?2C), is involved in RCC. In the present study, we examined which splice variants of LAMP?2 contributed to sunitinib resistance in RCC cells. In vitro analysis using ACHN, human RCC cell line, revealed that the IC50 of sunitinib was significantly increased by overexpression of LAMP?2A and LAMP?2B, but not LAMP?2C (P<0.01). Kaplan?Meier survival analysis using clinical samples revealed an association between shorter survival and high expression of LAMP?2A and LAMP?2B, but not LAMP?2C, in patients with RCC treated with sunitinib (P=0.01). Furthermore, high expression of LAMP?2A and LAMP?2B in RCC revealed a weak to moderate inverse correlation with the tumor shrinkage rate and progression?free survival, respectively. Thus, high expression of LAMP?2A and LAMP?2B contributed to the acquisition of sunitinib resistance, indicating that the expression of these two variants can predict the efficacy of sunitinib treatment in patients with RCC.

SUBMITTER: Nishikawa R

PROVIDER: S-EPMC7551029 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Splice variants of lysosome‑associated membrane proteins 2A and 2B are involved in sunitinib resistance in human renal cell carcinoma cells.

Nishikawa Ryoma R Osaki Mitsuhiko M Sasaki Ryo R Ishikawa Mizuho M Yumioka Tetsuya T Yamaguchi Noriya N Iwamoto Hideto H Honda Masashi M Kabuta Tomohiro T Takenaka Atsushi A Okada Futoshi F

Oncology reports 20200904 5

Sunitinib, a tyrosine kinase inhibitor, is among the first‑line treatments for metastatic or advanced stage renal cell carcinoma (RCC). However, patients with RCC develop resistance to sunitinib. We have previously demonstrated that lysosome‑associated membrane protein 2 (LAMP‑2), which has three splice variants with different functions (LAMP‑2A, LAMP‑2B, and LAMP‑2C), is involved in RCC. In the present study, we examined which splice variants of LAMP‑2 contributed to sunitinib resistance in RCC ...[more]

PMID: 32901843

Similar Datasets

Project description:As a recycling center, lysosomes are filled with numerous acid hydrolase enzymes that break down waste materials and invading pathogens. Recently, lysosomal cell death has been defined as "lysosomal membrane permeabilization and the consequent leakage of lysosome contents into cytosol." Here, we show that the neuraminidase (NA) of H5N1 influenza A virus markedly deglycosylates and degrades lysosome-associated membrane proteins (LAMPs; the most abundant membrane proteins of lysosome), which induces lysosomal rupture, and finally leads to cell death of alveolar epithelial carcinoma A549 cells and human tracheal epithelial cells. The NA inhibitors peramivir and zanamivir could effectively block the deglycosylation of LAMPs, inhibit the virus cell entry, and prevent cell death induced by the H5N1 influenza virus. The NA of seasonal H1N1 virus, however, does not share these characteristics. Our findings not only reveal a novel role of NA in the early stage of the H5N1 influenza virus life cycle but also elucidate the molecular mechanism of lysosomal rupture crucial for influenza virus induced cell death.The integrity of lysosomes is vital for maintaining cell homeostasis, cellular defense and clearance of invading pathogens. This study shows that the H5N1 influenza virus could induce lysosomal rupture through deglycosylating lysosome-associated membrane proteins (LAMPs) mediated by the neuraminidase activity of NA protein. NA inhibitors such as peramivir and zanamivir could inhibit the deglycosylation of LAMPs and protect lysosomes, which also further interferes with the H5N1 influenza virus infection at early stage of life cycle. This work is significant because it presents new concepts for NA's function, as well as for influenza inhibitors' mechanism of action, and could partially explain the high mortality and high viral load after H5N1 virus infection in human beings and why NA inhibitors have more potent therapeutic effects for lethal avian influenza virus infections at early stage.

Dataset Information

Splice variants of lysosome?associated membrane proteins 2A and 2B are involved in sunitinib resistance in human renal cell carcinoma cells.

Publications

Splice variants of lysosome‑associated membrane proteins 2A and 2B are involved in sunitinib resistance in human renal cell carcinoma cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets